Patients with any one of four different types of chronic renal failure (CRF) (glomerular disease, interstitial nephritis, diabetic nephropathy, or polycystic kidney disease) were observed during sequential determinations of glomerular filtration rate (GFR). Those whose GFR showed progression were either given ketoconazole 200 to 600 mg/day (to suppress cortisol production) plus prednisone 2.5 mg/day (to prevent anterior pituitary escape) and observed with the use of more GFR'S, or were observed while four more GFR's were determined before starting therapy with these drugs; some patients were subsequently withdrawn from these drugs and were observed with more GFR'S. The effect of these drugs on progression was estimated by a linear spline technique, using observations before, during, and (when available) after treatment. In 20 patients, sufficient data were obtained to estimate the magnitude of this effect. In seven patients with chronic glomerular disease, progressing at -0.62 1 0.12 ml/min/mo, progression slowed by 66% 1 12% (p < 0.01). In five patients with interstitial nephritis of various etiologies, progressing at -1.19 1 0.34 ml/min/mo, progression slowed by 55% 1 27% (p < 0.05). In five diabetic patients progressing at -1.22 1 0.14 ml/min/mo, progression slowed by an average of 77% + 14% (p < 0.01). In contrast, in four patients with polycystic kidney disease, progression accelerated by 99% 1 63%. Mean urinary steroid excretion decreased significantly; plasma corticotrophin did not increase. Neither proteinuria nor serum lipid levels changed. Urinary nitrate excretion decreased significantly, but serum nitrate did not change. Blood pressure decreased slightly (4.3 mm Hg). Three patients developed transiently elevated serum transaminase levels; two others withdrew because of side effects. We conclude that in chronic glomerular disease, diabetic nephropathy, and interstitial nephritis, this combination of drugs is as safe as ketoconazole in the absence of renal disease and shows promise of slowing progression. In polycystic kidney disease, it is apparaently ineffective or harmful.